The present invention relates to methods and apparatus for microwave-assisted chemistry techniques, and in particular to the use of microwaves in organic synthesis reactions. Most chemical reactions are generated, initiated, or accelerated by increasing temperature in accordance with relatively well-understood rate and thermodynamic principles. Accordingly, because microwaves can produce heat in certain qualifying substances, microwaves have been used to generate heat in a wide variety of chemical and chemistry related processes and techniques. These have typically included microwave drying for loss-on-drying moisture content analysis, and digestion of samples as a preparation step prior to other analytical techniques such as atomic absorption spectroscopy on the digested residues.
The carefully controlled conditions required for organic synthesis, however, generally have been unsuited (or vice versa) for use in typical earlier-generation microwave laboratory equipment. Specifically, although microwave devices can produce relatively large amounts of power, the nature of microwave cavities and the wavelength of microwaves tend to produce varying levels of power within the three dimensional space defined by the cavity. For large samples or samples where of high temperature effects are required or desired, this aspect of microwave heating does not matter and indeed permits microwaves to work better than most other types of heating for such purposes.
Chemical synthesis, however, and in particular organic synthesis, requires a more careful and to some extent delicate application of heat to chemical reactions. In response to the need for more carefully applied microwave energy for organic synthesis purposes (by way of example and not limitation), a number of newer devices have been developed which accomplish this purpose. The apparatus and instrument set forth in the above co-pending applications are exemplary of such a device, which has gained rapid acceptance as a method for carrying out organic synthesis using microwaves. The instrument is also commercially available under the DISCOVER™ trademark of CEM Corporation, Matthews, N.C., the assignee of the present invention. The success of the DISCOVER™ instrument has led to an increase in the use of microwave synthesis techniques, and the corresponding need for additional methods of carrying out synthetic reactions in this advantageous manner.
First, in order to scale up reactions from the laboratory bench top to useful synthesis of larger amounts, it is generally advantageous to use continuous rather than batch systems. Certain reactions are also carried out more advantageously in a flowing condition because of the nature of the catalysts used. As another issue, microwave penetration of materials tends to be effective, but spatially limited; i.e. microwaves tend to penetrate part of a sample, but no further. This spatial limitation can prevent optimum utilization of microwave power in a batch content. Stated differently, the lack of penetration depth can prevent microwave irradiation from affecting an entire batch sample with the result that interior portions of the sample are merely conductively or convectionally heated by the exterior portions.
Accordingly, a flow-through system that allows greater penetration by exposing a smaller volume to microwaves at any given time can be advantageous. Yet other reactions (e.g., esterification to produce polyesters) will move to an equilibrium condition, unless one of the reaction products is removed. In the case of the esterification reaction that produces polyester, water is removed in order to prevent an equilibrium from being established between the reactives and the products, thus encouraging the production of the finished esterified polyester, rather than an equilibrium mixture of reactants and products. Continuous flow reactors can be advantageous in accomplishing such reactions.
Continuous flow reactors can also help reduce the total forces (usually pressure) that can build up in batch reactions because a proportionally smaller volume is irradiated at any given time. Additionally, the speed with which microwaves interact with responsive materials (essentially instantaneously) makes flow-through techniques at reasonable rates feasible in situations where conventional heating would be too slow to be effective.
Microwaves are generally defined as those waves falling in the portion of the electromagnetic spectrum having frequencies of from about 300 to 300,000 megahertz (MHz). The corresponding wavelengths are on the order of between about one centimeter and one meter. These are of course arbitrary limits and will be understood as such. Most common instruments that incorporate microwave radiation use a preferred assigned frequency of 2450 megahertz.
As understood by those familiar with chemical reactions exposed to microwaves, the energy of microwave photons is relatively low compared to the typical energies of chemical bonds (80-120 Kcal/mole). Accordingly microwaves do not directly affect molecular structure, but instead tend to generate molecular rotations, and by the resulting kinetic energy typically generates heat. Microwave heating does not, however, depend on the thermal conductivity of the materials being heated, and thus offers an additional advantage over typical conduction heating methods.
Because of the speed with which microwaves can heat materials, the temperature of the sample (reactants, starting materials, etc.) can quickly increase beyond a desired or advantageous temperature. Accordingly, another desired aspect of a chemistry synthesis instrument, including a microwave-assisted instrument, is the capability of controlling temperature while a reaction proceeds. Lack of temperature control can produce a number of undesired consequences. First, the temperature may increase to a point at which the reactives or the products decompose rather than react properly. Secondly, if there are volatile products being generated by the reaction, which is typical in many organic synthesis reactions, the increased pressure must be contained or released. Alternatively, the increased pressure can change the reaction kinetics in an undesired manner. Finally, an increase in temperature can also produce physical consequences to the reaction vessels and the instrument itself should pressures and temperatures and pressures become so high as to create some sort of unintended mechanical or physical failure.
Temperature control is available for microwave instruments. For example, commonly assigned U.S. Pat. No. 6,227,041 illustrates how measuring the temperature of a sample can be used to moderate (typically reducing) the applied microwave power, and thus prevent a sample from overheating and decomposing.
All chemical reactions are driven by thermodynamic factors, and most are initiated when energy is added to the reactants. In many cases, microwave irradiation can apply energy to chemical reactants faster and more efficiently than conventional heating steps. Accordingly, when the microwave power is reduced or stopped in an effort to control temperature, the efficiency of the reaction can be reduced even as heat is being produced. Thus a reaction proceeding at an elevated temperature in the absence of microwaves can still be proceeding less-efficiently than it would if microwaves were being applied.
Accordingly, co-pending and commonly assigned application Ser. No. 10/064,261 filed Jun. 26, 2002, discloses an instrument for microwave synthesis that incorporates proactive cooling in a single-mode microwave cavity. By moderating the heat generated by the applied microwaves or the reaction itself, the instrument permits a greater amount of microwave power to be applied to the reaction as may be desired or necessary.
The instrument described in the '261 application is, however, a batch-type instrument rather than a continuous-flow device.
The general attraction of continuous flow chemistry is generally well understood in concept, and a number of attempts have been made to carry it out. For example, in commonly assigned U.S. Pat. No. 5,215,715, a sample is moved in the form of a slug on a continuous basis through a microwave heated digesting system. The same or similar system is used in commonly assigned U.S. Pat. No. 5,420,039. Other recent work includes U.S. Pat. No. 6,242,723 in which two separate sets of reactants can be moved into a vessel where they can react while remaining separated by an appropriate filter while being irradiated with microwaves. U.S. Pat. No. 6,316,759 discloses an apparatus for conducting gas chromatography while heating the columns using microwaves. U.S. Pat. No. 6,303,005 shows a distillation system that uses microwave heating. U.S. Pat. No. 5,672,316 shows a semi-flow through technique that has certain proactive temperature controls, the goal of the technique being to maintain a pressure equilibrium in high-pressure reactions. U.S. Pat. No. 5,382,414 shows a reaction vessel that includes a flow-through passage for use in a conventional microwave cavity.
U.S. Pat. No. 5,387,397 shows a flow-through system that merely incorporates a “microwave enclosure” or a “suitable cavity” rather than a single mode cavity. The '397 patent also incorporates a post-irradiation cooling element. The '397 patent thus fails to recognize the power density issues raised by conventional multi-mode cavities and likewise fails to recognize that the act of reducing microwave power to control temperature can correspondingly reduce the efficient progress (rate and yield) of certain chemical reactions.
In the scientific literature, several attempts have been carried out using a conventional microwave oven (rather than a specific instrument) in which a fixed bed reactor is placed in the cavity and exposed to microwaves as the reactants flow there through. These include Plazl, AlChE journal Volume 43, Number 3, March 1997 and Pipus, Chemical Engineering Journal 76 (2000) 239-245. Other flow-through techniques have used conventional cavities as well including reports by Braun, Microporous and Mesoporous Materials 23 (1998) 79-81 and Chemat, Journal of Microwave Power and Electromagnetic Energy, Volume 33, No. 2,1998, pages 88-94.
All of these, however, use the more typical large microwave cavity that applies large amounts of power, but at a low and spatially inconsistent power density in the manner discussed above, thus making successful flow-through techniques less likely and less reproducible.
Accordingly, there remains a need for a more elegant solution to the problem of conducting sensitive organic reactions at controlled temperatures while maximizing the available use of microwave energy in a desirable manner.